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Heart failure guidelines: What’s new?
Author’s Accepted Manuscript Heart failure guidelines: What's new? Lampros Papadimitriou, Carine E. Hamo, Javed Butler
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To appear in: Trends in Cardiovascular Medicine Cite this article as: Lampros Papadimitriou, Carine E. Hamo and Javed Butler, Heart failure guidelines: What's new?, Trends in Cardiovascular Medicine, http://dx.doi.org/10.1016/j.tcm.2017.01.003 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Heart failure guidelines: What’s new? Lampros Papadimitriou*, MD PhD , Carine E. Hamo, MD, Javed Butler, MD MPH MBA From the Division of Cardiology, Department of Medicine, Stony Brook University, Stony Brook, NY
*
Address for Correspondence: Lampros Papadimitriou, Division of Cardiology, Stony Brook
University, Health Sciences Center, T-16, Room 080, SUNY at Stony Brook, NY 11794, USA. Tel: 631 638 2201. Fax: 631 444 1054. Email:[email protected].
1
Abstract Heart Failure is a global epidemic, affecting approximately 5 million adults in the U.S.A. The cornerstone of contemporary pharmacological therapy targets the over activated reninangiotensin-aldosterone and sympathetic autonomic systems. The 2016 focused pharmacologic update on the current Heart Failure Guidelines introduces the use of two newly approved regimens valsartan/sacubitril and ivabradine. Over the last two decades, guideline directed medical therapy has accomplished significant improvement in survival rates among heart failure patients; however these novel compounds were reported to exert additional mortality and morbidity benefits, in heart failure subpopulations with reduced ejection fraction.
Keywords: valsartan/sacubitril, ivabradine, guidelines, heart failure
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Introduction Heart failure (HF) is a serious epidemic affecting around 5 million persons in the United States. There have been several new therapies and diagnostic techniques tested in these patients over the last few years. The target of these compounds has largely been the over activated renin-angiotensin-aldosterone and sympathetic pathways. It has been nearly a decade since the various randomized studies with novel molecules in HF have shown substantial decreases in clinical endpoints. Since the previous HF guidelines in 2013, the Food and Drug Administration (FDA) has approved two new medications for HF in 2015: valsartan/sacubitril (entresto) and ivabradine (corlanor). As a result, task Force members of the American College of Cardiology and the American Heart Association (ACC/AHA) and Heart Failure Society of America (HFSA) considered that there was a substantial need to issue a pharmacologic update on the current guidelines to address the two new medications and answer questions regarding when and under which circumstances they fit into present guideline directed medical therapy (GDMT) for HF. These recommendations apply to stage C patients, those with structural heart disease with prior or current symptoms of HF and with reduced Ejection Fraction (HFrEF). The level of evidence for both is B-R, since their recommendation is based on a single large multicenter randomized double-blind trial. The 2016 HF guidelines update is the first time that a collaborative effort was undertaken between the ACC/AHA and the HFSA. The update was announced at around the same time as the European Society of Cardiology guidelines were issued. However, this review will focus on the ACC/AHA update.
Valsartan/Sacubitril Valsartan/Sacubitril is a member of a novel pharmacologic category called angiotensinreceptor/neprilysin inhibitor (ARNI) consisting of the angiotensin receptor blocker (ARB) valsartan and the neprilysin inhibitor sacubitril. The pharmacologic name of this compound is LCZ696. LCZ696, soon after oral intake dissolves into valsartan, and a sacubitril prodrug, which then (within 3.5 hours from ingestion) enzymatically splits into the active drug. The half-lives of the active metabolite of the prodrug sacubitril and valsartan are 12 and 14 hours 3
respectively, while the bioavailability of valsartan in the combination pill is higher such that 103 mg twice daily of valsartan in the 200 mg twice daily of entresto regimen contains 160 mg twice daily valsartan equivalent in a singular preparation.(1)
Neprilysin is a membrane metalloendopeptidase involved in the degradation of several endogenous molecules, such as natriuretic peptides (NPs), angiotensin II, endothelin 1, adrenomedullin, opioids, bradykinin, glucagon and vasoactive intestinal peptide expressed in several tissues especially in the kidney. By blocking neprilysin, and subsequently the catabolism of the aforementioned molecules, their plasma levels increase; thus the adaptive/maladaptive mechanisms or signaling pathways of the respective substances are enhanced.(1) (2) Plasma accumulation of NP and specifically of atrial NP (ANP) and B-type NP (BNP) serves as a restorative mechanism against the increased atrial and ventricular pressures respectively, by enhancing systemic and kidney vasodilation and natriuresis, thus decreasing preload, afterload and total body sodium and fluid composition. Initially, neprilysin inhibitors, like candoxatril, and ecadotril were developed as individual drugs. They were tested in hypertension with disappointing results.(3, 4) This was partially explained by the concurrent accumulation of other substances, such as angiotensin II, which is also degraded by neprilysin, whose vasoconstrictive properties compete with the cardio-protective effects of natriuretic peptides (NPS). Based on these data, dual inhibitors of the renin-angiotensin system (RAS) and neprilysin were developed, as the addition of a RAS blocker would counter the neprilysin inhibition related elevation of angiotensin II. One of the first compounds in this category was omapatrilat, a combination of a neprilysin inhibitor with an angiotensin converting enzyme inhibitor (ACE-I). The Omapatrilat versus Enalapril Randomized Trial of Utility in Reducing events (OVERTURE) (5) tested the effect of omapatrilat vs. enalapril in 5770 subjects with HFrEF ejection fraction (EF) ≤30%) and New York Heart Association (NYHA) class II-IV symptoms. Although omapatrilat failed to meet the composite primary endpoint of all cause mortality or HF hospitalization [Hazard Ratio (HR)=0.94, p=0.187], it resulted in a significant reduction in the composite secondary endpoint of cardiovascular death and HF hospitalization (HR=0.91, p=0.024), but a higher 4
occurrence of angioedema. (5)The repeated increased rates of angioedema were also confirmed in the Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial, which assessed the effectiveness of omapatrilat vs. enalapril in hypertension.(6) As a result, the development of omapatrilat was stopped. The next product in this pipeline was valsartan/sacubitril, which established the new pharmacologic category of ARNIs. Its mechanism of action in HF is described in Figure 1.
Current Recommendations In the 2016 pharmacological update, valsartan/sacubitril received a class I level A recommendation for HFrEF with NYHA symptoms II-III. This was based on the Prospective Comparison of ARNI [Angiotensin Receptor–Neprilysin Inhibitor] with ACE-I [Angiotensin Converting Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM HF) trial, which was a double blind randomized trial of 8442 subjects with NYHA class II-IV symptoms and an EF ≤40% initially, which later changed to ≤35%. The main inclusion criteria of the trial are shown in table 1. History of hypersensitivity, allergy or intolerance to ACEI, ARB, known history of angioedema, glomerular filtration rate (GFR) <30ml/min/1.73m2, and serum potassium >5.2 and 5.4 mmol/l, before and at randomization were some of the main exclusion criteria. Mean age of the study population was 63.8±11 for both arms, mean EF was 29±6%, and 21.8% were females. At the time of randomization, subjects were receiving optimized medical treatment, including b-blockers (93%) and mineralocorticoid receptor antagonists (MRA) (60%). PARADIGM HF was a carefully designed trial with a double consecutive run-in phase with a total daily dose of enalapril 20mg, and valsartan/sacubitril 400mg, after up titrating from 200mg, and only the subjects who tolerated doses during the first two steps were then randomized to either enalapril 10mg twice daily vs valsartan/sacubitril 200mg twice daily. (7) During the run-in phase of enalapril and valsartan/sacubitril, 1102 and 977 subjects were discontinued respectively. The primary end point was a composite of death from cardiovascular causes or a first HF hospitalization, while the secondary endpoints included death from any cause. The trial was stopped early, after a median follow-up of 27 months, showing a 20% reduction in 5
death from cardiovascular causes and HF hospitalization. The separation of the two curves was seen early from day 30. Furthermore, valsartan/sacubitril decreased death from any cause, compared to enalapril by 16% (p-value <0.01). It is to be noted that in this study valsartan/sacubitril was compared to enalapril and not placebo. In a cost effectiveness study, based on the PARADIGM HF results, it was shown that for every 100.000 patients taking valsartan/sacubitril, there would be a decrease of approximately 3000 deaths and hospitalizations over a 2-year period. (8) The ACC/AHA recommended replacement with an ARNI for all patients with HFrEF who tolerated an ACE-I or ARB and had class II-III symptoms with acceptable blood pressure. Regarding the safe use of this new compound, the ACC/AHA issued a class III recommendation, not to use valsartan/sacubitril because of potential harm a) concomitantly with an ACE-I, and not to start the ARNI within 36 hours from the last dose of the latter and b) in subjects with a past medical history of angioedema. Both recommendations to avoid the use of valsartan/sacubitril were mainly driven by the previous experience with omapatrilat. Omapatrilat consists of a neprilysin inhibitor and an ACE-I, both of which block the degradation of bradykinin. On the contrary, valsartan/sacubitril consists of an ARB, which does not participate in bradykinin’s pathway, thus leading to a lesser increase in angioedema. Table 2 depicts the occurrence of angioedema in the major RAAS/neprilysin inhibitor trials (omapatrilat or valsartan/sacubitril). In addition, PARADIGM HF reported that valsartan/sacubitril was relatively safe compared to enalapril. The mean dose in the study was 375±75mg resulting in a statistically significant increase in hypotensive episodes (p<0.001) and a non-significant increase in angioedema episodes (19 vs 10 cases in valsartan/sacubitril and enalapril respectively). In the enalapril group a statistically higher number of subjects had an elevated creatinine (≥2.5mg/dl, p=0.007), hyperkalemia (>6.0mmol/l, p=0.007) and a higher occurrence of cough (p<0.001). (Table 3) Interestingly, according to a new analysis from Vardeny et al, (9) participants of PARADIGM-HF, who experienced hypotension during the run-in phase (enalapril or valsartan/sacubitril) and continued on randomization, sustained the same 6
cardioprotective benefits from the use of valsartan/sacubitril vs enalapril, compared to those without hypotensive episodes (HR=0.8 vs HR=0.77, interaction P=0.78). It should be highlighted that the PARADIGM HF trial excluded 5.6% vs 5.8% of patients in the enalapril and valsartan/sacubitril group respectively who had an adverse event in the pre-randomization/ run-in phase that led to the early discontinuation from the study.
Cost Effectiveness As with any new medication, there are concerns regarding the cost effectiveness of this new strategy. Gaziano et al, reported that with an annual cost of $4400, the gain from valsartan/sacubitril’s vs enalapril’s use would reach an incremental cost-effectiveness ratio (ICER) of $50.000 per quality-adjusted life-years (QALYs), which is considered a “very good value” for a new therapeutic strategy. (8) It was calculated, that due to the fewer hospitalizations, there would be medical savings of $27 million over a 2 year period.
Safety Since neprilysin is involved in the degradation pathway of beta-amyloid peptides, there are concerns about a potential interaction with Alzheimer disease and macular degeneration of the retina. There were no warning signals in PARADIGM-HF and OVERTURE. However, the FDA recommended the conduction of “A multicenter, randomized, double-blind, activecontrolled trial to evaluate the effects of valsartan/sacubitril compared to valsartan on cognitive function as assessed by comprehensive neurocognitive battery and PET imaging in patients with chronic heart failure with preserved ejection fraction” (10) which is being addressed by the Efficacy and Safety of valsartan/sacubitril Compared to Valsartan on Cognitive Function in Patients With Heart Failure and Preserved Ejection Fraction (PERSPECTIVE) trial. Additionally, serial Mini Mental State Examination (MMSE) testing is included in the currently ongoing Efficacy and Safety of valsartan/sacubitril Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction (PARAGON-HF) trial. (11)
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Table 4 highlights the recent joint recommendations on the use of valsartan/sacubitril compared to the key points from the respective FDA approved prescribing information.
Future Trials Valsartan/sacubitril is currently being tested in several ongoing/or planned trials with the goal of providing evidence towards the expansion of its use to subjects who are hospitalized, those with advanced HF, preserved ejection fraction (HFpEF) patients, and the post-infarction patients. The Prospective Comparison of ARNI with ARB on Management of Heart Failure with Preserved Ejection Fraction (PARAMOUNT) was a small study of 308 subjects with no hard endpoints testing the effects of valsartan/sacubitril vs valsartan in HFpEF patients (EF≥45%), showing a significant reduction in NTproBNP at 12 weeks (p=0.005), which however was not sustained at 24 weeks (p=0.2). (12) The larger scale PARAGON-HF will provide the definite answer on valsartan/sacubitril efficacy in HFpEF upon its completion in March 2019 (NCT01920711).
Ivabradine Background and Mechanism of action Ivabradine is a molecule blocking the funny (If) ion channels. These ion channels were discovered almost 40 years ago, located in the sinoatrial node (SAN), atrioventricular node (AVN) and the ventricular conduction system. (13)The current through this channel is a mixed inward sodium/potassium current, activated in hyperpolarization. The main subunits of the If channels are the hyperpolarization-activated cyclic nucleotide-gated channels (HCN), four isoforms of which have been described. The If channel plays a substantial role in the repetitive activity of the myocardial pacemaker cells, but also in heart rate by delaying diastolic depolarization of the SAN cells. (Figure 2) Their main advantage over the classic beta-blocker in managing heart rate (HR) is the lack of negative inotropism of the former.(14) Alinidine and zatebradine were the first If channel blocking molecules tested, but were soon abandoned because of a lack of clinical efficiency and the occurrence of side effects. Ivabradine has undergone several large-scale trials in various cardiovascular 8
conditions, shown to have no action on other receptors or ion channels of the cardiovascular system in therapeutic concentrations.(15) Ivabradine is metabolized by cytochrome CYP3A4; thus it should not be prescribed concurrently with known inhibitors of the aforementioned cytochrome, such as ketoconazole. Ivabradine’s half-life is 6 hours, and is advised to be administered during meals, because this increases plasma exposure and limits variations in serum concentrations.
Current Recommendations In the recent joint ACC/AHA HF guidelines update, ivabradine was given a IIa recommendation for symptomatic HFrEF subjects with NYHA class II-IV, who are already receiving GDMT, including a beta blocker at maximum tolerated dose and a HR >70bpm at rest, while in sinus rhythm. Table 4 The results of the Effects on Outcomes of Heart Rate Reduction by Ivabradine in Patients With Congestive Heart Failure: Is There an Influence of Beta-Blocker Dose? (SHIFT) Trial,(16) which came out in 2010, constitute the basis for the updated recommendation. Ivabradine was initially approved in Europe in 2005 for chronic stable angina in subjects with sinus rhythm and an intolerance to beta blockers. The European Medicines Agency (EMEA) extended the approval for use in HF in December 2011, while in the U.S.A. the FDA granted approval for HF in 2015. The SHIFT trial was a randomized double blind worldwide study with 6558 HFrEF subjects and a median follow up period of 22.9 months. The main inclusion criteria are shown in Table 5. Non-dihydropyridine calcium channel blockers and class I anti-arrhythmic drugs were not allowed at inclusion or during the study. The baseline characteristics of the study population reflected a mean age of 60.4±11.4 years old (with 11% being >75 years old), a mean EF 29.0%±5.1%, mean HR 79.9±9.6 bpm, while 24% were females and 68% had an ischemic etiology of HF. After the initial selection period, there was a run in phase, to confirm eligibility and clinical stability and then randomization was performed based on the site and the treatment with or without b-blocker. The starting dose was 5mg daily or placebo, with a target of 15mg if tolerated. At randomization, 89.5%, 60%, and 93% of the 9
patients were under b-blockers, MRAs, and ACEI or/and ARB. The mean dose of Ivabradine at 1 year was 13 mg daily, achieved a 9.1 beats per minute (bpm) and 8.1 bpm reduction at 1 year and at the end of the study, respectively, compared to placebo.(16) The primary endpoint, a composite of cardiovascular death or HF hospitalization was met with a HR of 0.82, 95% CI 0.75-0.90, P <0.0001. It was estimated that 26 patients would need treatment for 1 year to prevent one cardiovascular death or HF hospitalization. Death from HF was significantly lower in the ivabradine subgroup (HR=0.74, 95% CI 0.58-0.94, p=0.014), however all cause and cardiovascular mortality did not differ between the treated and placebo subjects. (16) Benefits were driven primarily by HF hospitalizations (HR=0.74, 95% CI 0.660.83, p <0.0001), while the same beneficial effect of ivabradine was also found in all cause and cardiovascular hospitalizations and in the secondary composite endpoint of either cardiovascular death, HF hospitalization or admission for non-fatal myocardial infarction (HR=0.82, 95% CI 0.74-0.89, p <0.0001).
Gaps in Evidence The mortality benefit of ivabradine is assumed to be attributed to the HR reduction, which is a well-known predictor of worse outcomes in HF. Beta blockers have the advantage of acting on the adrenergic beta receptors expressed in the entire body. Thus, their protective effect can be attributed not only to the decrease in HR, but also by adjusting both afterload and preload, through their vasoreactive properties, and their interaction with the production of renin. Beta-blockers suppress both the RAAS and sympathetic overactivation, while ivabradine suppresses only the latter. However, in the SHIFT trial, where 89% of participants were taking beta-blockers, ivabradine was still able to exert its beneficial effect on mortality and morbidity. In SHIFT however, only 26% of the patients were on the target doses of beta-blockers both in the treated and the control subgroups. In a separate subanalysis, ivabradine significantly reduced the composite primary endpoint in the subset of 10
subjects who were under <50% of target beta-blocker dose or no beta-blocker.(17) Interestingly, ivabradine significantly reduced only HF hospitalizations (fraction of the composite primary endpoint) when administered to subjects with ≥50% of target betablocker dose by 19% (p=0.021). (16) In the subgroup that was using higher doses of betablockers, there was a trend towards better outcomes, but with no statistical significance. The cut off value of 70 bpm in SHIFT, was also used in the Ivabradine for Patients with Stable Coronary Artery Disease and Left-ventricular Systolic Dysfunction (BEAUTIFUL) study. (18) The latter was a multicenter randomized study with ivabradine vs placebo in patients with stable coronary artery disease and EF<40%. This study did not meet its primary endpoint, a composite of cardiovascular death and hospitalization for acute myocardial infarction or HF. However, the subgroup of patients with a baseline HR>70bpm, showed a statistically significant improvement in the secondary endpoints of rehospitalizations for fatal or non-fatal myocardial infarction (HR=0.64, 95% CI 0.49-0.84, p=0.001) and coronary revascularization (HR=0.70, 95% CI 0.52-0.93, p=0.016).(18) In SHIFT, the reduction in the primary endpoint was present in the subgroup with a baseline HR higher than the median of 77bpm (HR=0.75, 95% CI 0.67-0.85, p for interaction=0.029).
Safety Ivabradine demonstrated a satisfactory safety profile in SHIFT. Overall, serious adverse events occurred at a higher rate among patients randomized to placebo (p=0.025). However, symptomatic, and asymptomatic bradycardia occurred at higher rates in the ivabradine group compared to placebo (p<0.0001), with no difference in hypotensive reactions. Likewise, bradycardia (symptomatic and asymptomatic) leading to permanent discontinuation of the study was more frequent with ivabradine. Because hyperpolarizationactivated cyclic nucleotide–gated (HCN) channels are involved in neuronal excitability and found among others in the retina, in SHIFT subjects in the ivabradine group experienced phosphenes (transient enhanced brightness in a restricted area of the visual field) at higher rates than placebo (3% vs 1%, p<0.0001).(16) Ivabradine was associated with a higher rate of 11
atrial fibrillation (9% with ivabradine vs 8% with placebo, p=0.012). This finding has to be elucidated with future more focused and randomized studies, since the conclusions on potential associations are controversial, especially in regards to the perioperative atrial fibrillation occurrence. (19)
Disclosures: LP, CEH report no disclosures. JB reports receiving research support from the National Institutes of Health, and European Union, and serve as a consultant to Amgen, Astra Zeneca, Bayer, Boehringer Ingelheim, Cardiocell, Gilead, Merck, Novartis, Relypsa, Z Pharma.
Support: None
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REFERENCES 1.
Vardeny O, Miller R, Solomon SD. Combined Neprilysin and Renin-Angiotensin System
Inhibition for the Treatment of Heart Failure. JACC: Heart Failure. 2014;2(6):663-70. 2.
Gordin JS, Fonarow GC. New medications for heart failure. Trends in cardiovascular
medicine. 2016;26(6):485-92. 3.
Ando S, Rahman MA, Butler GC, Senn BL, Floras JS. Comparison of candoxatril and
atrial natriuretic factor in healthy men. Effects on hemodynamics, sympathetic activity, heart rate variability, and endothelin. Hypertension (Dallas, Tex : 1979). 1995;26(6 Pt 2):1160-6. 4.
Cleland JGF, Swedberg K. Lack of efficacy of neutral endopeptidase inhibitor ecadotril
in heart failure. The Lancet.351(9116):1657-8. 5.
Packer M, Califf RM, Konstam MA, Krum H, McMurray JJ, Rouleau JL, et al.
Comparison of Omapatrilat and Enalapril in Patients With Chronic Heart Failure: The Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE). Circulation. 2002;106(8):920-6. 6.
Kostis J. Omapatrilat and enalapril in patients with hypertension: the Omapatrilat
Cardiovascular Treatment vs. Enalapril (OCTAVE) trial. American Journal of Hypertension. 2004;17(2):103-11. 7.
McMurray JJV, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, et al.
Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure. New England Journal of Medicine. 2014;371(11):993-1004. 8.
Gaziano TA, Fonarow GC, Claggett B, Chan WW, Deschaseaux-Voinet C, Turner SJ, et
al. Cost-effectiveness Analysis of Sacubitril/Valsartan vs Enalapril in Patients With Heart Failure and Reduced Ejection Fraction. JAMA cardiology. 2016;1(6):666-72. 9.
Vardeny O, Claggett B, Kachadourian J, Pearson SM, Packer M, Zile M, et al. Incidence,
Predictors, and Outcomes Associated with Hypotensive Episodes among Patients Receiving Sacubitril/Valsartan or Enalapril: The PARADIGM-HF Trial. Journal of cardiac failure.22(8):S34. 10.
New drug application approval letter. Valsartan/sacubitril. [press release]. 2015.
11.
McMurray JJ. Neprilysin inhibition to treat heart failure: a tale of science, serendipity,
and second chances. European journal of heart failure. 2015;17(3):242-7.
13
12.
Solomon SD, Zile M, Pieske B, Voors A, Shah A, Kraigher-Krainer E, et al. The
angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial. Lancet (London, England). 2012;380(9851):1387-95. 13.
Borer JS, Tavazzi L. Update on ivabradine for heart failure. Trends in cardiovascular
medicine. 2016;26(5):444-9. 14.
DiFrancesco D, Borer JS. The funny current: cellular basis for the control of heart rate.
Drugs. 2007;67 Suppl 2:15-24. 15.
Swedberg K, Komajda M, Bohm M, Borer JS, Ford I, Tavazzi L. Rationale and design of
a randomized, double-blind, placebo-controlled outcome trial of ivabradine in chronic heart failure: the Systolic Heart Failure Treatment with the I(f) Inhibitor Ivabradine Trial (SHIFT). European journal of heart failure. 2010;12(1):75-81. 16.
Swedberg K, Komajda M, Böhm M, Borer JS, Ford I, Dubost-Brama A, et al. Ivabradine
and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. The Lancet. 2010;376(9744):875-85. 17.
Swedberg K, Komajda M, Bohm M, Borer J, Robertson M, Tavazzi L, et al. Effects on
outcomes of heart rate reduction by ivabradine in patients with congestive heart failure: is there an influence of beta-blocker dose?: findings from the SHIFT (Systolic Heart failure treatment with the I(f) inhibitor ivabradine Trial) study. J Am Coll Cardiol. 2012;59(22):1938-45. 18.
Fox K, Ford I, Steg PG, Tendera M, Ferrari R. Ivabradine for patients with stable
coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial. The Lancet.372(9641):807-16. 19.
Lu Y, Li K, Liu XS, Zhang N, Li G, Liu T. Ivabradine and atrial fibrillation: A double-
edged sword. International Journal of Cardiology. 2016;223:182-5. 20.
DiFrancesco D. Funny channels in the control of cardiac rhythm and mode of action of
selective blockers. Pharmacological research. 2006;53(5):399-406. 21.
Rouleau JL, Pfeffer MA, Stewart DJ, Isaac D, Sestier F, Kerut EK, et al. Comparison of
vasopeptidase inhibitor, omapatrilat, and lisinopril on exercise tolerance and morbidity in patients with heart failure: IMPRESS randomised trial. Lancet (London, England). 2000;356(9230):615-20. 22.
Administration UFaD. New Drug Application approval letter. Ivabradine. 2015. 14
23.
2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart
Failure: An Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Journal of cardiac failure. 2016;22(9):659-69.
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FIGURE LEGENDS Figure 1. Schematic mechanism of action of valsartan/sacubitril in Heart Failure. Heart failure stimulates both the renin-angiotensin system and the natriuretic peptide system. LCZ696 is composed of 2 molecular moieties, the angiotensin receptor blocker valsartan and the neprilysin inhibitor prodrug sacubitril (AHU377). Valsartan blocks the angiotensin type I (AT1) receptor. Sacubitril is converted enzymatically to the active neprilysin inhibitor LBQ657, which inhibits neprilysin, an enzyme that breaks down atrial natriuretic peptide (ANP), brain (or B-type) natriuretic peptide (BNP), and C-type natriuretic peptide (CNP), as well as other vasoactive substances. N-terminal pro-BNP (NT-proBNP) is not a substrate for neprilysin. (Reproduced with permission from Vardeny et al)(1)
Figure 2. Mechanism of Action of Ivabradine. Ivabradine slows spontaneous activity by reducing specifically the rate of diastolic depolarization. Ivabradine inhibits If by reducing the If conductance, rather than by altering the activation curve. (Reproduced with permission from DiFrancesco et al) (20)
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Table 1. Paradigm HF Inclusion Criteria 1. Age 18 years or older 2. NYHA functional class II – IV 3. LVEF ≤ 35% (initially this was ≤ 40% but changed in a protocol amendment 4. Plasma BNP ≥150 pg/mL (or NT-proBNP ≥600 pg/mL) or a BNP ≥100 pg/mL (or NTproBNP ≥400 pg/mL) and a hospitalization for heart failure within the last 12 month 5. Treatment with a stable dose of an ACE inhibitor or an ARB equivalent to enalapril 10 mg/day for at least 4 weeks before the screening visit 6. Treatment with a stable dose of a beta-blocker for at least 4 weeks prior to the screening visit, unless contraindicated or not tolerated. Abbreviations: NYHA, New York Heart Association; LVEF, Left Ventricular Ejection Fraction; BNP, Brain Natriuretic Peptide; NT-pro-BNP, N-terminal pro-Brain Natriuretic Peptide; ACE, Angiotensin Converting Enzyme; ARB, Angiotensin Receptor Blocker
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Table 2. Occurrence of Angioedema in Major RAAS/Neprilysin Inhibitor (RAASNI) Trials Angioedema Control RAASNI Group Inhibitors N Group N 1 0
N
Population
Comparison
573
HFrEF
Lisinopril 20mg vs omapatrilat 40mg
5770
HFrEF
Enalapril 20mg vs omapatrilat 40mg
14 (0.5%)
24 (0.8%)
OCTAVE Trial (2004)(6)
25302
HTN
Enalapril 40mg vs omapatrilat 80†
86 (0.68%)
274* (2.17%)
PARAMOUNT Trial (2012)(12)
308
HFpEF
0
1
PARADIGMHF Trial (2014)(7)
8399
HFrEF
Valsartan 320 mg vs valsartan/sacubitril 400mg Enalapril 20mg vs valsartan/sacubitril 400mg
10 (0.23%)
19 (0.45%)§
IMPRESS Trial (2000)(21) OVERTURE Trial (2002)(5)
Comments
1 subject in control and 2 in RAASNI group required hospitalization 2 subjects in RAASNI group had airway compromise, both recovered without significant sequelae. Angioedema between control and RAASNI groups were 1.62% vs 5.54% and 0.81% vs 3.93% in African Americans and current smokers respectively
1 control vs 3 RAASNI group required hospitalization, without airway compromise, p=0.31 Abbreviations: RAAS, Renin-Angiotensin-Aldosterone System; RAASNI, Renin-AngiotensinAldosterone/Neprilysin Inhibitors; HFrEF, Heart Failure with Reduced Ejection Fraction; HFpEF, Heart Failure with Preserved Ejection Fraction * pvalue=<0.005; §
pvalue=0.13;
† OCTAVE trial had 3 study groups:1st randomized treatment applied to untreated patients, 2nd randomized treatment replaced current therapy, 3rd randomized treatment added to current therapy
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Table 3. Adverse Events During the Randomized Treatment of PARADIGM-HF(7) Event Symptomatic Hypotension Serum Creatinine ≥2.5mg/dl Serum Potasium≥6.0mmol/L Cough
Valsartan/Sacubitril
Enalapril
N(%)
N(%)
588(14.0)
388(9.2)
<0.001
139(3.3)
188(4.5)
<0.001
181(4.3)
236(5.6)
0.007
474(11.3)
601(14.3)
<0.001
10(10.2)
5(0.1)
0.19
6(0.1)
4(0.1)
0.52
3(0.1)
1(<0.1)
0.31
p-value
Angioedema No treatment or use of antihistamines only Other Treatment without hospitalization Hospitalization (No airway compromise was recorded)
19
Table 4. HF Guidelines and FDA approved Prescribing Information for Valsartan/Sacubitril and Ivabradine. (10, 22, 23)
Ivabradine
Valsartan/sacubitril
2016 ACC/AHA/HFSA Guidelines Class
Recommendations
I
Use of ACE inhibitors (Level of Evidence: A), OR ARBs (Level of Evidence: A), OR ARNI (Level of Evidence: B-R) in conjunction with evidence-based beta blockers, and aldosterone antagonists in selected patients, for patients with chronic HFrEF to reduce morbidity and mortality.
I
Replacement by an ARNI, in patients with chronic symptomatic HFrEF NYHA class II or III who tolerate an ACE inhibitor or ARB, to further reduce morbidity and mortality.
III
ARNI should not be administered concomitantly with ACE inhibitors or within 36 hours of the last dose of an ACE inhibitor.
III
ARNI should not be administered to patients with a history of angioedema
IIa
Ivabradine can be beneficial to reduce HF hospitalization for patients with symptomatic (NYHA class II-III) stable chronic HFrEF (LVEF ≤35%) who are receiving GDMT, including a beta blocker at maximum tolerated dose, and who are in sinus rhythm with a heart rate of 70 bpm or greater at rest.
FDA Approved Prescribing Information Indications
Contraindications
The fixed-dose combination of the neprilysin inhibitor sacubitril and the ARB valsartan is indicated to reduce the risk of Cardiovascular death and HF hospitalization in patients with HF with reduced ejection fraction
History of angioedema related to previous ACE inhibitor or ARB, concomitant use of ACE inhibitors, concomitant use of aliskiren in patients with diabetes. WARNING – pregnancy, hyperkalemia.
To reduce the risk of hospitalization for worsening HF in patients with stable, symptomatic chronic HF with LVEF ≤ 35% who are in sinus rhythm with resting HR ≥70 bpm and either are on maximally tolerated doses of beta-blockers or have a contraindication to beta-blocker use.
Acute decompensated HF; BP <90/50 mmHg; sick sinus syndrome or third-degree AV block, unless a functioning demand pacemaker is present; resting HR < 60 bpm prior to treatment; severe hepatic impairment; pacemaker dependence. WARNING – fetal toxicity.
Dosing
Start with 49/51 mg BID Double the dose after 2–4 weeks as tolerated to maintenance dose of 97/103 mg BID.
Renal/Hepatic Impairment: For patients not currently taking an ACEI or ARB, or for those with GFR <30 mL/min/1.73 m2 or moderate hepatic impairment, start with 24/26 mg BID
Start with 5 mg twice daily. After 2 weeks of treatment, adjust dose based on HR. Max is 7.5 mg BID. In conduction defects or in hemodynamic instability, start with 2.5 mg BID
Abbreviations: ACC, American College of Cardiology; ACE, Angiotensin Converting Enzyme; AHA, American Heart Association; ARB, Angiotensin Receptor Blocker; ARNI, Angiotensin Receptor- Neprilysin Inhibitor; FDA, US Food and Drug Administration; GDMT, Guideline Directed Medical Treatment; HF, Heart Failure; BP, Blood Pressure; bpm, beats per minute; ; HFrEF, Heart Failure with Reduced Ejection Fraction; HFSA, Heart Failure Society of America; HR, Heart Rate; NYHA, New York Heart Association; LVEF, Left Ventricular Ejection Fraction; BNP, Brain Natriuretic Peptide; NT-pro-BNP, Nterminal pro-Brain Natriuretic Peptide;
20
Table 5. SHIFT trial Main Inclusion Criteria 1. Age 18 years or older 2. LVEF ≤ 35%, NYHA functional class II – IV, stable for ≥4 weeks 3. Hospital HF Admission within past year 4. Sinus Rhythm with resting HR≥70bpm Abbreviations: NYHA, New York Heart Association; LVEF, Left Ventricular Ejection Fraction; HF, Heart Failure; HR, Heart Rate
21
Figure 1
Figure 2
22
Figure 2
23
www.elsevier.com/locate/tcm
PII: DOI: Reference:
S1050-1738(17)30004-X http://dx.doi.org/10.1016/j.tcm.2017.01.003 TCM6363
To appear in: Trends in Cardiovascular Medicine Cite this article as: Lampros Papadimitriou, Carine E. Hamo and Javed Butler, Heart failure guidelines: What's new?, Trends in Cardiovascular Medicine, http://dx.doi.org/10.1016/j.tcm.2017.01.003 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Heart failure guidelines: What’s new? Lampros Papadimitriou*, MD PhD , Carine E. Hamo, MD, Javed Butler, MD MPH MBA From the Division of Cardiology, Department of Medicine, Stony Brook University, Stony Brook, NY
*
Address for Correspondence: Lampros Papadimitriou, Division of Cardiology, Stony Brook
University, Health Sciences Center, T-16, Room 080, SUNY at Stony Brook, NY 11794, USA. Tel: 631 638 2201. Fax: 631 444 1054. Email:[email protected].
1
Abstract Heart Failure is a global epidemic, affecting approximately 5 million adults in the U.S.A. The cornerstone of contemporary pharmacological therapy targets the over activated reninangiotensin-aldosterone and sympathetic autonomic systems. The 2016 focused pharmacologic update on the current Heart Failure Guidelines introduces the use of two newly approved regimens valsartan/sacubitril and ivabradine. Over the last two decades, guideline directed medical therapy has accomplished significant improvement in survival rates among heart failure patients; however these novel compounds were reported to exert additional mortality and morbidity benefits, in heart failure subpopulations with reduced ejection fraction.
Keywords: valsartan/sacubitril, ivabradine, guidelines, heart failure
2
Introduction Heart failure (HF) is a serious epidemic affecting around 5 million persons in the United States. There have been several new therapies and diagnostic techniques tested in these patients over the last few years. The target of these compounds has largely been the over activated renin-angiotensin-aldosterone and sympathetic pathways. It has been nearly a decade since the various randomized studies with novel molecules in HF have shown substantial decreases in clinical endpoints. Since the previous HF guidelines in 2013, the Food and Drug Administration (FDA) has approved two new medications for HF in 2015: valsartan/sacubitril (entresto) and ivabradine (corlanor). As a result, task Force members of the American College of Cardiology and the American Heart Association (ACC/AHA) and Heart Failure Society of America (HFSA) considered that there was a substantial need to issue a pharmacologic update on the current guidelines to address the two new medications and answer questions regarding when and under which circumstances they fit into present guideline directed medical therapy (GDMT) for HF. These recommendations apply to stage C patients, those with structural heart disease with prior or current symptoms of HF and with reduced Ejection Fraction (HFrEF). The level of evidence for both is B-R, since their recommendation is based on a single large multicenter randomized double-blind trial. The 2016 HF guidelines update is the first time that a collaborative effort was undertaken between the ACC/AHA and the HFSA. The update was announced at around the same time as the European Society of Cardiology guidelines were issued. However, this review will focus on the ACC/AHA update.
Valsartan/Sacubitril Valsartan/Sacubitril is a member of a novel pharmacologic category called angiotensinreceptor/neprilysin inhibitor (ARNI) consisting of the angiotensin receptor blocker (ARB) valsartan and the neprilysin inhibitor sacubitril. The pharmacologic name of this compound is LCZ696. LCZ696, soon after oral intake dissolves into valsartan, and a sacubitril prodrug, which then (within 3.5 hours from ingestion) enzymatically splits into the active drug. The half-lives of the active metabolite of the prodrug sacubitril and valsartan are 12 and 14 hours 3
respectively, while the bioavailability of valsartan in the combination pill is higher such that 103 mg twice daily of valsartan in the 200 mg twice daily of entresto regimen contains 160 mg twice daily valsartan equivalent in a singular preparation.(1)
Neprilysin is a membrane metalloendopeptidase involved in the degradation of several endogenous molecules, such as natriuretic peptides (NPs), angiotensin II, endothelin 1, adrenomedullin, opioids, bradykinin, glucagon and vasoactive intestinal peptide expressed in several tissues especially in the kidney. By blocking neprilysin, and subsequently the catabolism of the aforementioned molecules, their plasma levels increase; thus the adaptive/maladaptive mechanisms or signaling pathways of the respective substances are enhanced.(1) (2) Plasma accumulation of NP and specifically of atrial NP (ANP) and B-type NP (BNP) serves as a restorative mechanism against the increased atrial and ventricular pressures respectively, by enhancing systemic and kidney vasodilation and natriuresis, thus decreasing preload, afterload and total body sodium and fluid composition. Initially, neprilysin inhibitors, like candoxatril, and ecadotril were developed as individual drugs. They were tested in hypertension with disappointing results.(3, 4) This was partially explained by the concurrent accumulation of other substances, such as angiotensin II, which is also degraded by neprilysin, whose vasoconstrictive properties compete with the cardio-protective effects of natriuretic peptides (NPS). Based on these data, dual inhibitors of the renin-angiotensin system (RAS) and neprilysin were developed, as the addition of a RAS blocker would counter the neprilysin inhibition related elevation of angiotensin II. One of the first compounds in this category was omapatrilat, a combination of a neprilysin inhibitor with an angiotensin converting enzyme inhibitor (ACE-I). The Omapatrilat versus Enalapril Randomized Trial of Utility in Reducing events (OVERTURE) (5) tested the effect of omapatrilat vs. enalapril in 5770 subjects with HFrEF ejection fraction (EF) ≤30%) and New York Heart Association (NYHA) class II-IV symptoms. Although omapatrilat failed to meet the composite primary endpoint of all cause mortality or HF hospitalization [Hazard Ratio (HR)=0.94, p=0.187], it resulted in a significant reduction in the composite secondary endpoint of cardiovascular death and HF hospitalization (HR=0.91, p=0.024), but a higher 4
occurrence of angioedema. (5)The repeated increased rates of angioedema were also confirmed in the Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial, which assessed the effectiveness of omapatrilat vs. enalapril in hypertension.(6) As a result, the development of omapatrilat was stopped. The next product in this pipeline was valsartan/sacubitril, which established the new pharmacologic category of ARNIs. Its mechanism of action in HF is described in Figure 1.
Current Recommendations In the 2016 pharmacological update, valsartan/sacubitril received a class I level A recommendation for HFrEF with NYHA symptoms II-III. This was based on the Prospective Comparison of ARNI [Angiotensin Receptor–Neprilysin Inhibitor] with ACE-I [Angiotensin Converting Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM HF) trial, which was a double blind randomized trial of 8442 subjects with NYHA class II-IV symptoms and an EF ≤40% initially, which later changed to ≤35%. The main inclusion criteria of the trial are shown in table 1. History of hypersensitivity, allergy or intolerance to ACEI, ARB, known history of angioedema, glomerular filtration rate (GFR) <30ml/min/1.73m2, and serum potassium >5.2 and 5.4 mmol/l, before and at randomization were some of the main exclusion criteria. Mean age of the study population was 63.8±11 for both arms, mean EF was 29±6%, and 21.8% were females. At the time of randomization, subjects were receiving optimized medical treatment, including b-blockers (93%) and mineralocorticoid receptor antagonists (MRA) (60%). PARADIGM HF was a carefully designed trial with a double consecutive run-in phase with a total daily dose of enalapril 20mg, and valsartan/sacubitril 400mg, after up titrating from 200mg, and only the subjects who tolerated doses during the first two steps were then randomized to either enalapril 10mg twice daily vs valsartan/sacubitril 200mg twice daily. (7) During the run-in phase of enalapril and valsartan/sacubitril, 1102 and 977 subjects were discontinued respectively. The primary end point was a composite of death from cardiovascular causes or a first HF hospitalization, while the secondary endpoints included death from any cause. The trial was stopped early, after a median follow-up of 27 months, showing a 20% reduction in 5
death from cardiovascular causes and HF hospitalization. The separation of the two curves was seen early from day 30. Furthermore, valsartan/sacubitril decreased death from any cause, compared to enalapril by 16% (p-value <0.01). It is to be noted that in this study valsartan/sacubitril was compared to enalapril and not placebo. In a cost effectiveness study, based on the PARADIGM HF results, it was shown that for every 100.000 patients taking valsartan/sacubitril, there would be a decrease of approximately 3000 deaths and hospitalizations over a 2-year period. (8) The ACC/AHA recommended replacement with an ARNI for all patients with HFrEF who tolerated an ACE-I or ARB and had class II-III symptoms with acceptable blood pressure. Regarding the safe use of this new compound, the ACC/AHA issued a class III recommendation, not to use valsartan/sacubitril because of potential harm a) concomitantly with an ACE-I, and not to start the ARNI within 36 hours from the last dose of the latter and b) in subjects with a past medical history of angioedema. Both recommendations to avoid the use of valsartan/sacubitril were mainly driven by the previous experience with omapatrilat. Omapatrilat consists of a neprilysin inhibitor and an ACE-I, both of which block the degradation of bradykinin. On the contrary, valsartan/sacubitril consists of an ARB, which does not participate in bradykinin’s pathway, thus leading to a lesser increase in angioedema. Table 2 depicts the occurrence of angioedema in the major RAAS/neprilysin inhibitor trials (omapatrilat or valsartan/sacubitril). In addition, PARADIGM HF reported that valsartan/sacubitril was relatively safe compared to enalapril. The mean dose in the study was 375±75mg resulting in a statistically significant increase in hypotensive episodes (p<0.001) and a non-significant increase in angioedema episodes (19 vs 10 cases in valsartan/sacubitril and enalapril respectively). In the enalapril group a statistically higher number of subjects had an elevated creatinine (≥2.5mg/dl, p=0.007), hyperkalemia (>6.0mmol/l, p=0.007) and a higher occurrence of cough (p<0.001). (Table 3) Interestingly, according to a new analysis from Vardeny et al, (9) participants of PARADIGM-HF, who experienced hypotension during the run-in phase (enalapril or valsartan/sacubitril) and continued on randomization, sustained the same 6
cardioprotective benefits from the use of valsartan/sacubitril vs enalapril, compared to those without hypotensive episodes (HR=0.8 vs HR=0.77, interaction P=0.78). It should be highlighted that the PARADIGM HF trial excluded 5.6% vs 5.8% of patients in the enalapril and valsartan/sacubitril group respectively who had an adverse event in the pre-randomization/ run-in phase that led to the early discontinuation from the study.
Cost Effectiveness As with any new medication, there are concerns regarding the cost effectiveness of this new strategy. Gaziano et al, reported that with an annual cost of $4400, the gain from valsartan/sacubitril’s vs enalapril’s use would reach an incremental cost-effectiveness ratio (ICER) of $50.000 per quality-adjusted life-years (QALYs), which is considered a “very good value” for a new therapeutic strategy. (8) It was calculated, that due to the fewer hospitalizations, there would be medical savings of $27 million over a 2 year period.
Safety Since neprilysin is involved in the degradation pathway of beta-amyloid peptides, there are concerns about a potential interaction with Alzheimer disease and macular degeneration of the retina. There were no warning signals in PARADIGM-HF and OVERTURE. However, the FDA recommended the conduction of “A multicenter, randomized, double-blind, activecontrolled trial to evaluate the effects of valsartan/sacubitril compared to valsartan on cognitive function as assessed by comprehensive neurocognitive battery and PET imaging in patients with chronic heart failure with preserved ejection fraction” (10) which is being addressed by the Efficacy and Safety of valsartan/sacubitril Compared to Valsartan on Cognitive Function in Patients With Heart Failure and Preserved Ejection Fraction (PERSPECTIVE) trial. Additionally, serial Mini Mental State Examination (MMSE) testing is included in the currently ongoing Efficacy and Safety of valsartan/sacubitril Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction (PARAGON-HF) trial. (11)
7
Table 4 highlights the recent joint recommendations on the use of valsartan/sacubitril compared to the key points from the respective FDA approved prescribing information.
Future Trials Valsartan/sacubitril is currently being tested in several ongoing/or planned trials with the goal of providing evidence towards the expansion of its use to subjects who are hospitalized, those with advanced HF, preserved ejection fraction (HFpEF) patients, and the post-infarction patients. The Prospective Comparison of ARNI with ARB on Management of Heart Failure with Preserved Ejection Fraction (PARAMOUNT) was a small study of 308 subjects with no hard endpoints testing the effects of valsartan/sacubitril vs valsartan in HFpEF patients (EF≥45%), showing a significant reduction in NTproBNP at 12 weeks (p=0.005), which however was not sustained at 24 weeks (p=0.2). (12) The larger scale PARAGON-HF will provide the definite answer on valsartan/sacubitril efficacy in HFpEF upon its completion in March 2019 (NCT01920711).
Ivabradine Background and Mechanism of action Ivabradine is a molecule blocking the funny (If) ion channels. These ion channels were discovered almost 40 years ago, located in the sinoatrial node (SAN), atrioventricular node (AVN) and the ventricular conduction system. (13)The current through this channel is a mixed inward sodium/potassium current, activated in hyperpolarization. The main subunits of the If channels are the hyperpolarization-activated cyclic nucleotide-gated channels (HCN), four isoforms of which have been described. The If channel plays a substantial role in the repetitive activity of the myocardial pacemaker cells, but also in heart rate by delaying diastolic depolarization of the SAN cells. (Figure 2) Their main advantage over the classic beta-blocker in managing heart rate (HR) is the lack of negative inotropism of the former.(14) Alinidine and zatebradine were the first If channel blocking molecules tested, but were soon abandoned because of a lack of clinical efficiency and the occurrence of side effects. Ivabradine has undergone several large-scale trials in various cardiovascular 8
conditions, shown to have no action on other receptors or ion channels of the cardiovascular system in therapeutic concentrations.(15) Ivabradine is metabolized by cytochrome CYP3A4; thus it should not be prescribed concurrently with known inhibitors of the aforementioned cytochrome, such as ketoconazole. Ivabradine’s half-life is 6 hours, and is advised to be administered during meals, because this increases plasma exposure and limits variations in serum concentrations.
Current Recommendations In the recent joint ACC/AHA HF guidelines update, ivabradine was given a IIa recommendation for symptomatic HFrEF subjects with NYHA class II-IV, who are already receiving GDMT, including a beta blocker at maximum tolerated dose and a HR >70bpm at rest, while in sinus rhythm. Table 4 The results of the Effects on Outcomes of Heart Rate Reduction by Ivabradine in Patients With Congestive Heart Failure: Is There an Influence of Beta-Blocker Dose? (SHIFT) Trial,(16) which came out in 2010, constitute the basis for the updated recommendation. Ivabradine was initially approved in Europe in 2005 for chronic stable angina in subjects with sinus rhythm and an intolerance to beta blockers. The European Medicines Agency (EMEA) extended the approval for use in HF in December 2011, while in the U.S.A. the FDA granted approval for HF in 2015. The SHIFT trial was a randomized double blind worldwide study with 6558 HFrEF subjects and a median follow up period of 22.9 months. The main inclusion criteria are shown in Table 5. Non-dihydropyridine calcium channel blockers and class I anti-arrhythmic drugs were not allowed at inclusion or during the study. The baseline characteristics of the study population reflected a mean age of 60.4±11.4 years old (with 11% being >75 years old), a mean EF 29.0%±5.1%, mean HR 79.9±9.6 bpm, while 24% were females and 68% had an ischemic etiology of HF. After the initial selection period, there was a run in phase, to confirm eligibility and clinical stability and then randomization was performed based on the site and the treatment with or without b-blocker. The starting dose was 5mg daily or placebo, with a target of 15mg if tolerated. At randomization, 89.5%, 60%, and 93% of the 9
patients were under b-blockers, MRAs, and ACEI or/and ARB. The mean dose of Ivabradine at 1 year was 13 mg daily, achieved a 9.1 beats per minute (bpm) and 8.1 bpm reduction at 1 year and at the end of the study, respectively, compared to placebo.(16) The primary endpoint, a composite of cardiovascular death or HF hospitalization was met with a HR of 0.82, 95% CI 0.75-0.90, P <0.0001. It was estimated that 26 patients would need treatment for 1 year to prevent one cardiovascular death or HF hospitalization. Death from HF was significantly lower in the ivabradine subgroup (HR=0.74, 95% CI 0.58-0.94, p=0.014), however all cause and cardiovascular mortality did not differ between the treated and placebo subjects. (16) Benefits were driven primarily by HF hospitalizations (HR=0.74, 95% CI 0.660.83, p <0.0001), while the same beneficial effect of ivabradine was also found in all cause and cardiovascular hospitalizations and in the secondary composite endpoint of either cardiovascular death, HF hospitalization or admission for non-fatal myocardial infarction (HR=0.82, 95% CI 0.74-0.89, p <0.0001).
Gaps in Evidence The mortality benefit of ivabradine is assumed to be attributed to the HR reduction, which is a well-known predictor of worse outcomes in HF. Beta blockers have the advantage of acting on the adrenergic beta receptors expressed in the entire body. Thus, their protective effect can be attributed not only to the decrease in HR, but also by adjusting both afterload and preload, through their vasoreactive properties, and their interaction with the production of renin. Beta-blockers suppress both the RAAS and sympathetic overactivation, while ivabradine suppresses only the latter. However, in the SHIFT trial, where 89% of participants were taking beta-blockers, ivabradine was still able to exert its beneficial effect on mortality and morbidity. In SHIFT however, only 26% of the patients were on the target doses of beta-blockers both in the treated and the control subgroups. In a separate subanalysis, ivabradine significantly reduced the composite primary endpoint in the subset of 10
subjects who were under <50% of target beta-blocker dose or no beta-blocker.(17) Interestingly, ivabradine significantly reduced only HF hospitalizations (fraction of the composite primary endpoint) when administered to subjects with ≥50% of target betablocker dose by 19% (p=0.021). (16) In the subgroup that was using higher doses of betablockers, there was a trend towards better outcomes, but with no statistical significance. The cut off value of 70 bpm in SHIFT, was also used in the Ivabradine for Patients with Stable Coronary Artery Disease and Left-ventricular Systolic Dysfunction (BEAUTIFUL) study. (18) The latter was a multicenter randomized study with ivabradine vs placebo in patients with stable coronary artery disease and EF<40%. This study did not meet its primary endpoint, a composite of cardiovascular death and hospitalization for acute myocardial infarction or HF. However, the subgroup of patients with a baseline HR>70bpm, showed a statistically significant improvement in the secondary endpoints of rehospitalizations for fatal or non-fatal myocardial infarction (HR=0.64, 95% CI 0.49-0.84, p=0.001) and coronary revascularization (HR=0.70, 95% CI 0.52-0.93, p=0.016).(18) In SHIFT, the reduction in the primary endpoint was present in the subgroup with a baseline HR higher than the median of 77bpm (HR=0.75, 95% CI 0.67-0.85, p for interaction=0.029).
Safety Ivabradine demonstrated a satisfactory safety profile in SHIFT. Overall, serious adverse events occurred at a higher rate among patients randomized to placebo (p=0.025). However, symptomatic, and asymptomatic bradycardia occurred at higher rates in the ivabradine group compared to placebo (p<0.0001), with no difference in hypotensive reactions. Likewise, bradycardia (symptomatic and asymptomatic) leading to permanent discontinuation of the study was more frequent with ivabradine. Because hyperpolarizationactivated cyclic nucleotide–gated (HCN) channels are involved in neuronal excitability and found among others in the retina, in SHIFT subjects in the ivabradine group experienced phosphenes (transient enhanced brightness in a restricted area of the visual field) at higher rates than placebo (3% vs 1%, p<0.0001).(16) Ivabradine was associated with a higher rate of 11
atrial fibrillation (9% with ivabradine vs 8% with placebo, p=0.012). This finding has to be elucidated with future more focused and randomized studies, since the conclusions on potential associations are controversial, especially in regards to the perioperative atrial fibrillation occurrence. (19)
Disclosures: LP, CEH report no disclosures. JB reports receiving research support from the National Institutes of Health, and European Union, and serve as a consultant to Amgen, Astra Zeneca, Bayer, Boehringer Ingelheim, Cardiocell, Gilead, Merck, Novartis, Relypsa, Z Pharma.
Support: None
12
REFERENCES 1.
Vardeny O, Miller R, Solomon SD. Combined Neprilysin and Renin-Angiotensin System
Inhibition for the Treatment of Heart Failure. JACC: Heart Failure. 2014;2(6):663-70. 2.
Gordin JS, Fonarow GC. New medications for heart failure. Trends in cardiovascular
medicine. 2016;26(6):485-92. 3.
Ando S, Rahman MA, Butler GC, Senn BL, Floras JS. Comparison of candoxatril and
atrial natriuretic factor in healthy men. Effects on hemodynamics, sympathetic activity, heart rate variability, and endothelin. Hypertension (Dallas, Tex : 1979). 1995;26(6 Pt 2):1160-6. 4.
Cleland JGF, Swedberg K. Lack of efficacy of neutral endopeptidase inhibitor ecadotril
in heart failure. The Lancet.351(9116):1657-8. 5.
Packer M, Califf RM, Konstam MA, Krum H, McMurray JJ, Rouleau JL, et al.
Comparison of Omapatrilat and Enalapril in Patients With Chronic Heart Failure: The Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE). Circulation. 2002;106(8):920-6. 6.
Kostis J. Omapatrilat and enalapril in patients with hypertension: the Omapatrilat
Cardiovascular Treatment vs. Enalapril (OCTAVE) trial. American Journal of Hypertension. 2004;17(2):103-11. 7.
McMurray JJV, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, et al.
Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure. New England Journal of Medicine. 2014;371(11):993-1004. 8.
Gaziano TA, Fonarow GC, Claggett B, Chan WW, Deschaseaux-Voinet C, Turner SJ, et
al. Cost-effectiveness Analysis of Sacubitril/Valsartan vs Enalapril in Patients With Heart Failure and Reduced Ejection Fraction. JAMA cardiology. 2016;1(6):666-72. 9.
Vardeny O, Claggett B, Kachadourian J, Pearson SM, Packer M, Zile M, et al. Incidence,
Predictors, and Outcomes Associated with Hypotensive Episodes among Patients Receiving Sacubitril/Valsartan or Enalapril: The PARADIGM-HF Trial. Journal of cardiac failure.22(8):S34. 10.
New drug application approval letter. Valsartan/sacubitril. [press release]. 2015.
11.
McMurray JJ. Neprilysin inhibition to treat heart failure: a tale of science, serendipity,
and second chances. European journal of heart failure. 2015;17(3):242-7.
13
12.
Solomon SD, Zile M, Pieske B, Voors A, Shah A, Kraigher-Krainer E, et al. The
angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial. Lancet (London, England). 2012;380(9851):1387-95. 13.
Borer JS, Tavazzi L. Update on ivabradine for heart failure. Trends in cardiovascular
medicine. 2016;26(5):444-9. 14.
DiFrancesco D, Borer JS. The funny current: cellular basis for the control of heart rate.
Drugs. 2007;67 Suppl 2:15-24. 15.
Swedberg K, Komajda M, Bohm M, Borer JS, Ford I, Tavazzi L. Rationale and design of
a randomized, double-blind, placebo-controlled outcome trial of ivabradine in chronic heart failure: the Systolic Heart Failure Treatment with the I(f) Inhibitor Ivabradine Trial (SHIFT). European journal of heart failure. 2010;12(1):75-81. 16.
Swedberg K, Komajda M, Böhm M, Borer JS, Ford I, Dubost-Brama A, et al. Ivabradine
and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. The Lancet. 2010;376(9744):875-85. 17.
Swedberg K, Komajda M, Bohm M, Borer J, Robertson M, Tavazzi L, et al. Effects on
outcomes of heart rate reduction by ivabradine in patients with congestive heart failure: is there an influence of beta-blocker dose?: findings from the SHIFT (Systolic Heart failure treatment with the I(f) inhibitor ivabradine Trial) study. J Am Coll Cardiol. 2012;59(22):1938-45. 18.
Fox K, Ford I, Steg PG, Tendera M, Ferrari R. Ivabradine for patients with stable
coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial. The Lancet.372(9641):807-16. 19.
Lu Y, Li K, Liu XS, Zhang N, Li G, Liu T. Ivabradine and atrial fibrillation: A double-
edged sword. International Journal of Cardiology. 2016;223:182-5. 20.
DiFrancesco D. Funny channels in the control of cardiac rhythm and mode of action of
selective blockers. Pharmacological research. 2006;53(5):399-406. 21.
Rouleau JL, Pfeffer MA, Stewart DJ, Isaac D, Sestier F, Kerut EK, et al. Comparison of
vasopeptidase inhibitor, omapatrilat, and lisinopril on exercise tolerance and morbidity in patients with heart failure: IMPRESS randomised trial. Lancet (London, England). 2000;356(9230):615-20. 22.
Administration UFaD. New Drug Application approval letter. Ivabradine. 2015. 14
23.
2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart
Failure: An Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Journal of cardiac failure. 2016;22(9):659-69.
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FIGURE LEGENDS Figure 1. Schematic mechanism of action of valsartan/sacubitril in Heart Failure. Heart failure stimulates both the renin-angiotensin system and the natriuretic peptide system. LCZ696 is composed of 2 molecular moieties, the angiotensin receptor blocker valsartan and the neprilysin inhibitor prodrug sacubitril (AHU377). Valsartan blocks the angiotensin type I (AT1) receptor. Sacubitril is converted enzymatically to the active neprilysin inhibitor LBQ657, which inhibits neprilysin, an enzyme that breaks down atrial natriuretic peptide (ANP), brain (or B-type) natriuretic peptide (BNP), and C-type natriuretic peptide (CNP), as well as other vasoactive substances. N-terminal pro-BNP (NT-proBNP) is not a substrate for neprilysin. (Reproduced with permission from Vardeny et al)(1)
Figure 2. Mechanism of Action of Ivabradine. Ivabradine slows spontaneous activity by reducing specifically the rate of diastolic depolarization. Ivabradine inhibits If by reducing the If conductance, rather than by altering the activation curve. (Reproduced with permission from DiFrancesco et al) (20)
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Table 1. Paradigm HF Inclusion Criteria 1. Age 18 years or older 2. NYHA functional class II – IV 3. LVEF ≤ 35% (initially this was ≤ 40% but changed in a protocol amendment 4. Plasma BNP ≥150 pg/mL (or NT-proBNP ≥600 pg/mL) or a BNP ≥100 pg/mL (or NTproBNP ≥400 pg/mL) and a hospitalization for heart failure within the last 12 month 5. Treatment with a stable dose of an ACE inhibitor or an ARB equivalent to enalapril 10 mg/day for at least 4 weeks before the screening visit 6. Treatment with a stable dose of a beta-blocker for at least 4 weeks prior to the screening visit, unless contraindicated or not tolerated. Abbreviations: NYHA, New York Heart Association; LVEF, Left Ventricular Ejection Fraction; BNP, Brain Natriuretic Peptide; NT-pro-BNP, N-terminal pro-Brain Natriuretic Peptide; ACE, Angiotensin Converting Enzyme; ARB, Angiotensin Receptor Blocker
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Table 2. Occurrence of Angioedema in Major RAAS/Neprilysin Inhibitor (RAASNI) Trials Angioedema Control RAASNI Group Inhibitors N Group N 1 0
N
Population
Comparison
573
HFrEF
Lisinopril 20mg vs omapatrilat 40mg
5770
HFrEF
Enalapril 20mg vs omapatrilat 40mg
14 (0.5%)
24 (0.8%)
OCTAVE Trial (2004)(6)
25302
HTN
Enalapril 40mg vs omapatrilat 80†
86 (0.68%)
274* (2.17%)
PARAMOUNT Trial (2012)(12)
308
HFpEF
0
1
PARADIGMHF Trial (2014)(7)
8399
HFrEF
Valsartan 320 mg vs valsartan/sacubitril 400mg Enalapril 20mg vs valsartan/sacubitril 400mg
10 (0.23%)
19 (0.45%)§
IMPRESS Trial (2000)(21) OVERTURE Trial (2002)(5)
Comments
1 subject in control and 2 in RAASNI group required hospitalization 2 subjects in RAASNI group had airway compromise, both recovered without significant sequelae. Angioedema between control and RAASNI groups were 1.62% vs 5.54% and 0.81% vs 3.93% in African Americans and current smokers respectively
1 control vs 3 RAASNI group required hospitalization, without airway compromise, p=0.31 Abbreviations: RAAS, Renin-Angiotensin-Aldosterone System; RAASNI, Renin-AngiotensinAldosterone/Neprilysin Inhibitors; HFrEF, Heart Failure with Reduced Ejection Fraction; HFpEF, Heart Failure with Preserved Ejection Fraction * pvalue=<0.005; §
pvalue=0.13;
† OCTAVE trial had 3 study groups:1st randomized treatment applied to untreated patients, 2nd randomized treatment replaced current therapy, 3rd randomized treatment added to current therapy
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Table 3. Adverse Events During the Randomized Treatment of PARADIGM-HF(7) Event Symptomatic Hypotension Serum Creatinine ≥2.5mg/dl Serum Potasium≥6.0mmol/L Cough
Valsartan/Sacubitril
Enalapril
N(%)
N(%)
588(14.0)
388(9.2)
<0.001
139(3.3)
188(4.5)
<0.001
181(4.3)
236(5.6)
0.007
474(11.3)
601(14.3)
<0.001
10(10.2)
5(0.1)
0.19
6(0.1)
4(0.1)
0.52
3(0.1)
1(<0.1)
0.31
p-value
Angioedema No treatment or use of antihistamines only Other Treatment without hospitalization Hospitalization (No airway compromise was recorded)
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Table 4. HF Guidelines and FDA approved Prescribing Information for Valsartan/Sacubitril and Ivabradine. (10, 22, 23)
Ivabradine
Valsartan/sacubitril
2016 ACC/AHA/HFSA Guidelines Class
Recommendations
I
Use of ACE inhibitors (Level of Evidence: A), OR ARBs (Level of Evidence: A), OR ARNI (Level of Evidence: B-R) in conjunction with evidence-based beta blockers, and aldosterone antagonists in selected patients, for patients with chronic HFrEF to reduce morbidity and mortality.
I
Replacement by an ARNI, in patients with chronic symptomatic HFrEF NYHA class II or III who tolerate an ACE inhibitor or ARB, to further reduce morbidity and mortality.
III
ARNI should not be administered concomitantly with ACE inhibitors or within 36 hours of the last dose of an ACE inhibitor.
III
ARNI should not be administered to patients with a history of angioedema
IIa
Ivabradine can be beneficial to reduce HF hospitalization for patients with symptomatic (NYHA class II-III) stable chronic HFrEF (LVEF ≤35%) who are receiving GDMT, including a beta blocker at maximum tolerated dose, and who are in sinus rhythm with a heart rate of 70 bpm or greater at rest.
FDA Approved Prescribing Information Indications
Contraindications
The fixed-dose combination of the neprilysin inhibitor sacubitril and the ARB valsartan is indicated to reduce the risk of Cardiovascular death and HF hospitalization in patients with HF with reduced ejection fraction
History of angioedema related to previous ACE inhibitor or ARB, concomitant use of ACE inhibitors, concomitant use of aliskiren in patients with diabetes. WARNING – pregnancy, hyperkalemia.
To reduce the risk of hospitalization for worsening HF in patients with stable, symptomatic chronic HF with LVEF ≤ 35% who are in sinus rhythm with resting HR ≥70 bpm and either are on maximally tolerated doses of beta-blockers or have a contraindication to beta-blocker use.
Acute decompensated HF; BP <90/50 mmHg; sick sinus syndrome or third-degree AV block, unless a functioning demand pacemaker is present; resting HR < 60 bpm prior to treatment; severe hepatic impairment; pacemaker dependence. WARNING – fetal toxicity.
Dosing
Start with 49/51 mg BID Double the dose after 2–4 weeks as tolerated to maintenance dose of 97/103 mg BID.
Renal/Hepatic Impairment: For patients not currently taking an ACEI or ARB, or for those with GFR <30 mL/min/1.73 m2 or moderate hepatic impairment, start with 24/26 mg BID
Start with 5 mg twice daily. After 2 weeks of treatment, adjust dose based on HR. Max is 7.5 mg BID. In conduction defects or in hemodynamic instability, start with 2.5 mg BID
Abbreviations: ACC, American College of Cardiology; ACE, Angiotensin Converting Enzyme; AHA, American Heart Association; ARB, Angiotensin Receptor Blocker; ARNI, Angiotensin Receptor- Neprilysin Inhibitor; FDA, US Food and Drug Administration; GDMT, Guideline Directed Medical Treatment; HF, Heart Failure; BP, Blood Pressure; bpm, beats per minute; ; HFrEF, Heart Failure with Reduced Ejection Fraction; HFSA, Heart Failure Society of America; HR, Heart Rate; NYHA, New York Heart Association; LVEF, Left Ventricular Ejection Fraction; BNP, Brain Natriuretic Peptide; NT-pro-BNP, Nterminal pro-Brain Natriuretic Peptide;
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Table 5. SHIFT trial Main Inclusion Criteria 1. Age 18 years or older 2. LVEF ≤ 35%, NYHA functional class II – IV, stable for ≥4 weeks 3. Hospital HF Admission within past year 4. Sinus Rhythm with resting HR≥70bpm Abbreviations: NYHA, New York Heart Association; LVEF, Left Ventricular Ejection Fraction; HF, Heart Failure; HR, Heart Rate
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Figure 1
Figure 2
22
Figure 2
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